Alzheimer's disease is the most common form of senile dementia and the fourth highest cause of disability and death in the elderly. It is characterized by the presence of three main brain hallmarks viz. diffuse neuronal loss with a particular involvement of the cholinergic system, extracellular protein deposits (amyloid plaques) and intracellular protein deposits (neurofibrillary tangles, NFTs). All current therapies are based on the cholinergic hypothesis and demonstrate only symptomatic treatment. Progression of the disease is not slowed or halted, with symptoms continuing to deteriorate over time. The amyloid hypothesis proposes that Alzheimer's disease is caused by an imbalance between Amyloid β production and clearance, resulting in increased amounts of Amyloid β in various forms such as monomers, oligomers, insoluble fibrils and plaques in the CNS. The rate of Amyloid β production is same as that in healthy volunteers; whereas rate of clearance is impaired by 25-30%. High levels of Amyloid β then initiate cascade of events culminating in neuronal damage and death manifesting as progressive dementia of the Alzheimer's disease type. Evidence shows that insufficient clearance of the Amyloid β protein is a prime cause in over 95% of Alzheimer's disease patients (Mawuenyega, K. G. et al. Science 2010, 330, 1774). Further it is known that Amyloid β efflux is mediated by p-glycoprotein efflux pump. The p-glycoprotein deficiency at the blood-brain barrier increases Amyloid β deposition in an Alzheimer's disease (Cirrito, J. R. et al., J. Clin. Invest. 2005, 115, 3285). P-glycoprotein (P-glycoprotein) is highly expressed on the luminal surface of brain capillary endothelial cells and contributes to the BBB. In P-glycoprotein-null mice, [125I]-Amyloid β40 and [125I]-Amyloid β42 microinjected into the CNS clear at half the rate that they do in WT mice. When amyloid precursor protein-transgenic (APP-transgenic) mice were administered a P-glycoprotein inhibitor, Amyloid β levels within the brain interstitial fluid significantly increased within hours of treatment. APP-transgenic, P-glycoprotein-null mice had increased levels of brain Amyloid β and enhanced Amyloid β deposition compared with APP-transgenic, P-glycoprotein WT mice. These data establish a direct link between P-glycoprotein and Amyloid β metabolism in vivo and suggest that P-glycoprotein activity at the BBB could affect risk for developing Alzheimer's disease as well as provide a novel diagnostic and therapeutic target (Lam, F. C. et al., J. Neurochem. 2001, 76, 1121). Thus it is evident that drugs that have ability to increase levels of P-glycoprotein should increase amyloid clearance. Fascaplysin (1) is a fused benzoyl-linked beta-carbolinium alkaloid isolated from marine sponge Fascaplysinopsis Bergquist sp. collected in the South Pacific near the Fiji Island as an unusual antimicrobial pigment (Roll, D. M. et al., J. Org. Chem. 1988, 53, 3276). It showed inhibition of the growth of several microbes, including Staphylococcus aureus, Escherichia coli, Candida albicans, and Saccharomyces cerevisiae. It showed suppression in the proliferation of mouse leukemia cells L-1210 with ED50=0.2 μM (Roll, D. M. et al., J. Org. Chem. 1988, 53, 3276) and also exhibited selectivity in murine tumor cytotoxicity assay (Segraves, N. L. et al., Tetrahedron Lett. 2003, 44, 3471). Fascaplysin exhibited anti-proliferation effect towards human cervical cancer HeLa cells through induction of apoptosis via extrinsic death pathway and mitochondrial pathway, but not arresting cell cycle progression at G1 phase (Lu, X. et al., Yaoxue Xuebao 2009, 44, 980). Fascaplysin showed promising specific CDK-4 inhibitory activity with IC50 of 0.35 μM and it also blocked the growth of cancer cells at the G0/G1 phase of the cell cycle (Soni, R. et al., Biochem. Biophys. Res. Commun. 2000, 275, 877; Segraves, N. L. et al., J. Nat. Prod. 2004, 67, 783; Soni, R. et al., Biochem. Biophys. Res. Commun. 2000, 272, 794; Soni, R. et al., J. Natl. Cancer Inst. 2001, 93, 436; for review, see: Bharate, S. B. et al., Mini-Rev. Med. Chem. 2012, 12, 650). Fascaplysin also displayed inhibition of acetylcholinesterase (AChE) with IC50 value of 1.49 μM (Bharate, S. B. et al., Med. Chem. Commun. 2012, 3, 1098).
